Table 2.

Evidence-based studies correlating Thuja occidentalis targeting molecular cascades underlying mechanisms of diabetic nephropathy and neuropathy.

S. No	Active Constituents	Evidenced studies of natural Phytochemicals possessing anti-inflammatory and anti-apoptotic activity	Phytochemistry of Thuja occidentalis	Proposed mechanism of Thuja occidentalis targeting signaling cascades involved in diabetic nephropathy and neuropathy	References
1.	Thujone	The anti-inflammatory effect of thujone has been evaluated in C57BL/6 mice (metastasis model) induced by injecting highly metastatic B16F-10 melanoma cells into mice; the administration of thujone resulted in suppression of the NF-κB pathway and decreased levels of tumor cell proliferation, adhesion, and invasion molecules involving matrix metalloproteinase, extracellular signal-regulated kinase (ERK)-1, ERK-2, MAPK and vascular endothelial growth factor (VEGF) were decreased in metastatic animals.	Thuja occidentalis comprises the active ingredient 65 % Thujone (85 % α-thujone and 15 % β-thujone)	Based on the evidence, Thuja occidentalis's anti-inflammatory activity is shown by nephropathy by inhibiting the NF-κB and decreasing the levels of down-regulating the expression of matrix metalloproteinase, extracellular signal-regulated kinase (ERK), MAPK pathway and vascular endothelial growth factor (VEGF) and pro-inflammatory mediators causing damage of renal and peripheral nerves.	18, 30, 37, 38,39,40,41
2.	Fenchone	IN SILICO studies evaluated the apoptotic activity of fenchone. The interaction of Fenchone with anti-apoptotic proteins Bcl-2 and Bcl-XL showed higher interaction with Bcl2 & BAX than tends to be effective in inhibiting the pro-apoptotic proteins and having anti-apoptotic properties. Furthermore, the antioxidant and anti-inflammatory property of fenchone was also evaluated by using a rat model was induced nephrotoxicity by using doxorubicin (Dox), the administration of limonene showed a preventive effect against Dox-induced renal damage. It decreased the expression of NF-κB, COX-2, iNOS, and nitric oxide.	Thuja occidentalis comprises the active ingredient Fenchone in a concentration of 1.4–4 %.	Therefore, the anti-apoptotic activity of Thuja occidentalis comprising Fenchone has been proposed for preventing apoptotic cell death in renal damage and peripheral nerve damage by decreasing the levels of pro-apoptotic proteins that provide the correlation of mitochondrial oxidative stress and apoptosis in diabetic nephropathy ad neuropathy. Therefore, the treatment with Thuja occidentalis could be an effective strategy in preventing mitochondrial oxidative stress-mediated apoptotic death with decreased levels of pro-apoptotic proteins (Bcl-2 and Bcl-XL). Furthermore, the anti-inflammatory property of the Thuja occidentalis mechanism has been showed as beneficial therapy in preventing diabetic neuropathy and nephropathy by inhibiting the NF-κB and decreasing the levels of pro-inflammatory mediators causing damage to renal and peripheral nerves.	6,42
3.	Borneol	Borneol active component was evaluated against neuroblastoma cells (SH-SY5Y) and showed neuroprotective by inhibiting the oxidative stress and the up regulation of nrf2. Borneol also showed to be effective in inhibiting the MAPK/p38, PI3L/Akt signaling pathway as evidenced in various studies.	Thuja occidentalis comprises the active ingredient borneol in a concentration of 1.4–4 %.	Thuja occidentalis tends to be effective in hyperglycemia-induced nephropathy and neuropathy by up-regulating the Nrf2 molecule that transcribes the antioxidant enzymes glutathione (GSH) and superoxide dismutase (SOD) and presents the oxidative stress in diabetes-induced renal and peripheral damage. One of the most likely factors representing oxidative stress in diabetes-induced renal and peripheral damage is the downregulation of Nrf2. Also, the active constituent borneol showed the anti-inflammatory and anti-apoptotic activity by inhibiting the MAPK/p38, PI3L/Akt signaling pathway involved in pathology of neuropathy and nephropathy.	43, 44, 45,46,47, 48, 49,42
4.	Camphene	The apoptotic activity of camphene was evaluated in t-BHP-stressed rats induced oxidative stress. The administration of camphene showed anti-oxidative stress by preventing the mitochondrial membrane potential and inhibiting the release of cytochrome C-mediated apoptosis.	Thuja occidentalis comprises the active ingredient camphene in a concentration of 1.4–4 %.	Thuja occidentalis tends to be effective in hyperglycemia-induced nephropathy and neuropathy by preventing mitochondrial oxidative stress and mitochondrial dysfunction is the principal cause of free radicals (ROS/NS) and is associated with apoptosis-mediated renal and peripheral nerves damage in diabetes as a complication that is marked with up-regulation of apoptotic proteins including Bcl2/Bax ratio and caspase-3 levels. Therefore, it may show the beneficial effect of Thuja occidentalis in diabetic neuropathy and nephropathy by preventing mitochondrial oxidative stress and apoptosis along with decreased Bcl2/Bax ratio and caspase-3 levels.	50, 51, 52,53,54
5.	Limonene	The antioxidant and anti-inflammatory properties of limonene were evaluated using a rat model that induced nephrotoxicity by using doxorubicin (Dox). The administration of limonene showed a preventive effect against Dox-induced renal damage, decreasing the expression of NF-κB, COX-2, iNOS, and nitric oxide.	Thuja occidentalis comprises the active ingredient borneol in a concentration of 1.4–4 %.	Therefore, the Thuja occidentalis mechanism has been showed as beneficial therapy in preventing diabetic neuropathy and nephropathy by inhibiting the NF-κB and decreasing the levels of pro-inflammatory mediators causing damage to renal and peripheral nerves.	55, 56, 57
6.	Myrcene	The antioxidant and anti-inflammatory property of Myrcene was evaluated by using the rat model as the administration of Myrcene inhibits the NF-κB expression and downregulates the pro-inflammatory cytokines (COX-2, iNOS, IL-1β, IL-6, and TNF-α). Additionally, the Myrcene active constituent is evidenced to inhibits the JAK-STAT (Janus kinase-signal transducer and activator of transcription) pathway and the MAPK/P38 (mitogen-activated protein kinase) pathway. Preventing apoptosis and inflammation	Thuja occidentalis comprises the active ingredient Myrcene in a concentration of 1.4–4 %.	Based on the evidence, it has been showed that Thuja occidentalis is an effective therapy in preventing diabetic neuropathy and nephropathy with a mechanism of inhibition of NF-κB and decreasing the pro-inflammatory mediators' levels causing renal damage and peripheral nerves. Further, the evidence indicating that Myrcene inhibits the JAK-STAT and MAPK/P38 pathways, thereby preventing apoptosis and inflammation, suggests potential therapeutic benefits in diabetes-related neuropathy and nephropathy.	58,59
7.	Terpinolene	The In Silico studies evaluated the apoptotic activity of fenchone. The interaction of terpinolene with anti-apoptotic proteins Bcl-2 and Bcl-XL showed higher interaction with Bcl2 & BAX than tends to be effective in inhibiting the pro-apoptotic proteins and having anti-apoptotic properties.	Thuja occidentalis comprises the active ingredient borneol in a concentration of 1.4–4 %.	Therefore, the anti-apoptotic activity of Thuja occidentalis comprising Fenchone has been proposed for preventing apoptotic cell death in renal damage and peripheral nerve damage by decreasing the levels of pro-apoptotic proteins that provide the correlation of mitochondrial oxidative stress and apoptosis in diabetic nephropathy ad neuropathy. Therefore, the treatment with Thuja occidentalis could be an effective strategy in preventing mitochondrial oxidative stress-mediated apoptotic death with decreased levels of pro-apoptotic proteins (Bcl-2 and Bcl-XL).	42
8.	kaempferol	The apoptotic activity of kaempferol was evaluated by IN SILICO studies. The interaction of terpinolene with anti-apoptotic proteins Bcl-2 and Bcl-XL showed higher interaction with Bcl2 & BAX than tends to be effective in inhibiting the pro-apoptotic proteins and having anti-apoptotic properties. Kaempferol has been evidenced in various studies to inhibit the inflammatory signaling pathway of NF-kB, MAPK/P38 and activates the Nrf2 suggested its anti-inflammatory, anti-oxidant and anti-apoptotic property.	Thuja occidentalis comprises the active ingredient kaempferol.	Therefore, the anti-apoptotic activity of Thuja occidentalis comprising kaempferol has been proposed to prevenapoptotic cell death in renal damage and peripheral nerve damage by decreasing the pro-apoptotic proteins that provide the correlation of mitochondrial oxidative stress and apoptosis in diabetic nephropathy ad neuropathy. Therefore, the treatment with Thuja occidentalis could be an effective strategy in preventing mitochondrial oxidative stress-mediated apoptotic death with decreased levels of pro-apoptotic proteins (Bcl-2 and Bcl-XL). Additionally, the Kaempferol, a flavonoid found in Thuja occidentalis, may mitigate diabetes neuropathy and nephropathy by inhibiting NF-kB and MAPK/P38 pathways, reducing inflammation, and activating the Nrf2 pathway to counter oxidative stress and apoptosis. Its multifaceted actions suggest potential therapeutic benefits in alleviating symptoms and halting the progression of these diabetic complications.	27,60,61,62,63,64,42,54
9.	Proanthocyanidins	The natural component proanthocyanidins has been evaluated in cell culture studies and provided evidence of reduction of BCL-2 levels and prevented the apoptosis process. Along with it, proanthocyanidins also showed effectiveness in reducing inflammation by inhibiting c-Jun N-terminal kinase (JNK), p38, extracellular signal-regulated kinase (ERK), PI3K/Akt, nuclear factor-κB (NF-κB) signaling pathways involved in inflammation.	Thuja occidentalis comprises the active ingredient kaempferol.	Therefore, the Thuja occidentalis as anti-apoptotic resulted by preventing the mitochondrial oxidative stress-mediated apoptotic death with decreased pro-apoptotic proteins (Bcl-2 and Bcl-XL) mediated cell death in renal damage and peripheral nerve damage. Furthermore, the anti-inflammatory property of Thuja occidentalis has also been showed by inhibiting the c-Jun N-terminal kinase (JNK), p38, extracellular signal-regulated kinase (ERK), Akt, nuclear factor-κB (NF-κB) inflammatory signaling pathways involved in renal and peripheral nerve damage.	65,63,66,67,68,57, 59, 69, 70